Although recent clinical and experimental observations indicate the existence of a mutual relationship between the nervous and the immune system, the molecular mechanisms by which the two systems interact are just beginning to be studied. Neuropeptides that belong to the tachykinin family, such as substance-P, neurokinin A, and neurokinin B, could play an important immunoregulatory role in vivo, based on the following observations: a) the presence of SP and NKA in the lymphoid organs; b) the existence of SP receptors on lymphocytes; and c) the in vitro immunomodulatory activity of SP and NKA. The major objective of this proposal is to determine whether SP and related neurokinins modulate the immune response through the regulation of cytokine expression. Preliminary results indicated that: a) SP induced the production of IL-2 in murine T cell lines and murine normal lymphocyte cell cultures in a dose-dependent and specific manner; b) SP induced de novo synthesis of IL-2; and c) SP induced the expression of IFNgamma in murine splenocytes, in the absence or presence of suboptimal doses of ConA. We propose to continue and expand the molecular analysis of the immunoregulatory activity of SP and related neurokinins by: a) investigating the molecular mechanisms, including transcriptional and posttranscriptional regulation, by which SP and NKA stimulate IL-2 and IFNgamma production in murine splenocytes and T cell lines; b) investigating the cellular target(s) for SP action within the normal lymphocyte/macrophage population, and the intercellular communications leading to IL-2 or IFNgamma production as a result of SP stimulation; c) studying the expression of SP receptors in murine T lymphocytes. The study of the molecular mechanisms by which neuropeptides regulate the expression of interleukins, and therefore affect the outcome of the immune response, will offer new insights in the immunomodulatory activity of the nervous system in normal and pathological conditions. This could lead to new ways of controlling and manipulating the activity of the immune system, which in turn could become significant for the development of new treatments for AIDS patients.